Much evidence exists to support the interrelationship between dysfunction of the monoamine neurotransmitter systems, stress and the onset of depressive illness. For years research suggested disruption of the noradrenergic response to stress as the predisposing factor in depression. This was based on animal studies describing depletion of norepinephrine (NE) in response to severe stressors coupled with clinical evidence that many compounds which increased NE were effective in reducing the symptoms associated with this disorder. Due in part to the many adverse side effects associated with tricyclic antidepressants, newer more selective compounds were developed and the success of the serotonin (5-HT) selective reuptake inhibitors (SSRIs) as antidepressants shifted the focus of the field to re-examine the role of serotonin in depression. This is the most widely prescribed class of antidepressants today. However, there is a paucity in the knowledge of how all antidepressants exert therapeutic action. A continued effort to understand the mechanism of action of antidepressants is now focused on the interrelationship of NE and 5-HT. The proposed research program will attempt to provide evidence for important interactions between these two neurotransmitter systems that may help to explain the ability of diverse pharmacological agents to exert similar clinical benefits. Specifically, studies will examine the hypothesis that even though selective neuronal transporter inhibitors may act specifically when administered acutely, they will have indirect actions on other systems following chronic administration. This ability to alter multiple monoamine systems after chronic drug administration may account for the delay in therapeutic effects. Additionally, a nonselective reuptake inhibitor, venlafaxine, will be compared with the NE-selective inhibitor reboxetine and the 5-HT selective reuptake inhibitor fluoxetine to determine whether there is a basis for nonselective monoamine reuptake inhibition to confer greater therapeutic benefits. In addition, experiments will be performed to examine the hypothesis that both 5-HT and NE systems mediate behavioral responses to swim stressor. Furthermore, the impact of chronic antidepressant treatment on the behavioral responses and neurochemical effects associated with the swim stressor will be explored. The results of the proposed studies will provide insight into neuronal adaptations of two monoamine neurotransmitter systems that have been implicated in depression and be useful in the development of therapeutic agents for the treatment of depression.